Fluorination process

Abstract

A process for fluorination of a fluoride acceptor species comprising contacting an organofluorine species with a base to provide a fluoride donor species and contacting the fluoride donor species with the fluoride acceptor species to form a fluorinated species. The organofluorine species can be a species of formula (1): R1R2HC-CFR3R4; (1a): R1R2C=CFR3, or a fluoroarene; wherein R1, R2, R3 and R4 are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl.

Description

[0001] FLUORINATION PROCESS

[0002] The invention relates to a process for fluorination of a fluoride acceptor species comprising contacting an organofluorine species with a base to provide a fluoride donor species and contacting the fluoride donor species with the fluoride acceptor species to form a fluorinated species. The present invention further provides a process for fluorination of a fluoride acceptor species comprising contacting the fluoride acceptor species with a fluoride donor composition, as well as use of a fluoride donor composition as a fluorinating agent, and a system comprising a fluoride donor composition and a fluoride acceptor.

[0003] BACKGROUND

[0004] Fluorinated species hold importance across a spectrum of scientific and industrial applications due to their unique properties and versatile functionalities. Their significance stems from the remarkable stability and chemical inertness conferred by the carbonfluorine bond, making fluorinated compounds invaluable in pharmaceuticals, materials science, agrochemicals, and more. In pharmaceutical research, the introduction of fluorine atoms into drug molecules often enhances biological activity, metabolic stability, and membrane permeability, leading to the development of safer and more effective therapeutics. Additionally, fluorinated materials exhibit exceptional properties such as low surface energy, thermal stability, and resistance to chemicals, making them indispensable in coatings, lubricants, electronic devices, and speciality polymers. Moreover, fluorinated agrochemicals play a crucial role in crop protection, where their unique properties enable the formulation of potent pesticides and herbicides with enhanced efficacy and environmental safety profiles.

[0005] Many fluorinated species are produced using fluorinating agents. Fluorinating agents are capable of the introduction of fluorine atoms into various compounds to synthesise fluorinated species. These agents, characterised by their ability to facilitate fluorination reactions, play a pivotal role in medicinal chemistry, material science, and agrochemical research due to the unique properties conferred by fluorine atoms. Their diverse applications span from pharmaceutical development, where the introduction of fluorine can enhance drug efficacy and metabolic stability, to the synthesis of fluorinated polymers with tailored properties.

[0006] The fluorine content of most fluorinating agents is derived from calcium fluoride, commonly known as fluorspar, a naturally occurring mineral. Calcium fluoride serves as a primary source for the production of fluorine gas or hydrogen fluoride, which are subsequently utilised in the synthesis of numerous fluorinating agents through various chemical processes. However, calcium fluoride is a finite natural resource, and its extraction poses significant environmental concerns. The process of harvesting calcium fluoride involves mining operations, which can result in habitat destruction, soil erosion, and water pollution due to the release of heavy metals and other contaminants into surrounding ecosystems. Additionally, the energy-intensive nature of mining and processing calcium fluoride further exacerbates its environmental footprint, leading to greenhouse gas emissions and exacerbating climate change. As such, the reliance on calcium fluoride as a primary source for fluorine compounds underscores the urgency for sustainable alternatives.

[0007] Hydrofluorocarbons (HFCs) and chlorofluorocarbons (CFCs) are classes of organofluorine species which are of particular environmental concern. These organofluorine species are widely used in various industrial applications, particularly as refrigerants, propellants, and solvents. CFCs, once widely used in refrigeration and aerosol propellants, are notorious for their role in depleting the ozone layer. HFCs were introduced as replacements for CFCs due to their ozone-friendly properties. However, it was later discovered that HFCs are potent greenhouse gases. Furthermore, per- and polyfluoroalkyl substances (PFAS) are organofluorine species which are known for their persistence in the environment and bioaccumulative properties, which pose significant ecological and human health risks. PFAS have been linked to adverse effects on wildlife, including reproductive and developmental issues, as well as potential adverse health effects in humans, such as immune system disruption and certain types of cancer.

[0008] There is therefore a need to address the above problems. SUMMARY

[0009] The present invention is based on the surprising realisation that organofluorine species, such as HFCs or CFCs, can be efficiently used as the source of fluorine in the preparation of fluorine containing compounds, which allows for the recycling and repurposing of waste organofluorine species, as well as the conservation of finite natural resources.

[0010] A first aspect provides a process for the fluorination of a fluoride acceptor species comprising: providing an organofluorine species having a structure according to formula (1) or (1a), wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, alkylamino, or aryl: or wherein the organofluorine species is an optionally substituted fluoroarene; , ; contacting the organofluorine species with a base to provide a fluoride donor species; and contacting the fluoride donor species with the fluoride acceptor species to form a fluorinated species. Preferably, the organofluorine species has a structure according to formula (1) or (1a). More preferably the organofluorine species has a structure according to formula (1 ) - in which case, the process for the fluorination of a fluoride acceptor species comprises: providing an organofluorine species having a structure according to formula (1) wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, alkylamino, or aryl: contacting the organofluorine species with a base to provide a fluoride donor species; and contacting the fluoride donor species with the fluoride acceptor species to form a fluorinated species.

[0011] A second aspect provides a process for fluorination of a fluoride acceptor species comprising contacting the fluoride acceptor species with a fluoride donor composition for the fluorination of a fluoride acceptor, the composition formed from a mixture of: an organofluorine species having a structure according to formula (1) or (1a), wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, alkylamino, or aryl: or wherein the organofluorine species is an optionally substituted fluoroarene; , ; and a base. Preferably, the organofluorine species has a structure according to formula (1) or (1 a). More preferably the organofluorine species has a structure according to formula (1) - in which case, the process for fluorination of a fluoride acceptor species comprises contacting the fluoride acceptor species with a fluoride donor composition for the fluorination of a fluoride acceptor, the composition formed from a mixture of: an organofluorine species having a structure according to formula (1) wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, alkylamino, or aryl: and a base.

[0012] A third aspect provides the use of a fluoride donor composition as a fluorinating agent, wherein the fluoride donor composition comprises: an organofluorine species having a structure according to formula (1) or (1a), wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, alkylamino, or aryl: or wherein the organofluorine species is an optionally substituted fluoroarene; , ■ and a base. Preferably, the organofluorine species has a structure according to formula (1) or (1 a). More preferably the organofluorine species has a structure according to formula (1) - in which case, the use is the use of a fluoride donor composition as a fluorinating agent, wherein the fluoride donor composition comprises: an organofluorine species having a structure according to formula (1) wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, alkylamino, or aryl: and a base.

[0013] A fourth aspect provides a system comprising a fluoride donor composition and a fluoride acceptor; wherein the fluoride donor composition comprises an organofluorine species having a structure according to formula (1) or (1a), wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, alkylamino, or aryl: or wherein the organofluorine species is an optionally substituted fluoroarene; , ; and a base; and wherein the fluoride donor composition and a fluoride acceptor are not mixed, or are premixed. Preferably, the organofluorine species has a structure according to formula (1) or (1a). More preferably the organofluorine species has a structure according to formula (1) - in which case, the system comprises a fluoride donor composition and a fluoride acceptor; wherein the fluoride donor composition comprises an organofluorine species having a structure according to formula (1) wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, alkylamino, or aryl: and a base; and wherein the fluoride donor composition and a fluoride acceptor are not mixed, or are premixed.

[0014] A fifth aspect provides a fluorinating agent prepared or preparable by contacting an organofluorine species having a structure according to formula (1) or (1a) wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: or wherein the organofluorine species is an optionally substituted fluoroarene; , ; with a base. Preferably, the organofluorine species has a structure according to formula (1) or (1 a). More preferably the organofluorine species has a structure according to formula (1). Preferably, the organofluorine species has a structure according to formula (1) or (1 a). More preferably the organofluorine species has a structure according to formula (1) - in which case, the fluorinating agent is prepared or preparable by contacting an organofluorine species having a structure according to formula (1) wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl:

[0015] (i) ; with a base.

[0016] BRIEF DESCRIPTION OF THE FIGURES

[0017] Figure 1 shows two19F NMR spectra taken before (top) and after (bottom) a deprotonation of (2,4,6-CeH2F3)2CHCF3 using lithium hexamethyldisilazide;

[0018] Figure 2 shows a19F NMR spectrum taken after a process using (2,4,6-CeH2F3)2CHCF3as the organofluorine species, potassium hexamethyldisilazide as the base, and tosyl chloride as the fluoride acceptor species. A peak corresponding to tosyl fluoride is highlighted;

[0019] Figure 3 shows a19F NMR spectrum taken after a process using 1 ,1 ,1 -trifluoroethane as the organofluorine species, potassium hexamethyldisilazide as the base, and tosyl chloride as the fluoride acceptor species. A peak corresponding to tosyl fluoride is labelled; Figure 4 shows a19F NMR spectrum taken after a process using 1 ,1 ,1 ,2-tetrafluoroethane as the organofluorine species, potassium hexamethyldisilazide as the base, and tosyl chloride as the fluoride acceptor species. A peak corresponding to tosyl fluoride is labelled;

[0020] Figure 5 shows a19F NMR spectrum taken after a process using 1 ,1 -difluoroethane as the organofluorine species, potassium hexamethyldisilazide as the base, and tosyl chloride as the fluoride acceptor species. A peak corresponding to tosyl fluoride is labelled; and

[0021] Figure 6 shows a scanning electron microscope image of in situ generated KF taken after a process using (2,4,6-CeH2F3)2CHCF3 as the organofluorine species, potassium hexamethyldisilazide as the base.

[0022] DETAILED DESCRIPTION

[0023] For the purposes of the present invention, the following terms as used herein shall, unless otherwise indicated, be understood to have the following meanings. Other terms that are not specifically defined below are to be understood as having their normal meaning in the art.

[0024] The term “organofluorine species” refers to an organic compound comprising at least one carbon-fluorine bond.

[0025] The term “fluoride acceptor species” as used herein, refers to a reactant which is capable of forming a bond to a fluoride ion in order to form a new species comprising said fluoride ion, or an ionic species in which a fluoride ion displaces an anion. Typically, the fluoride acceptor species will be an electrophile which undergoes nucleophilic substitution with the fluoride ion. Typically, the fluoride acceptor species will comprise a leaving group which may be replaced with the fluoride ion.

[0026] The term “fluoride donor species” as used herein, refers to a species formed in situ by the reaction of the organofluorine species with a base, and optionally one or more further additives to provide a species capable of donating a fluoride ion to a fluoride acceptor species.

[0027] The term “substituted” as used herein, in the context of a chemical structure describes a group being bonded to any other atom or functional group other than hydrogen. The term “unsubstituted” as used herein, in the context of a chemical structure describes a group being bonded to no other atom or functional group except hydrogen.

[0028] The term "alkyl" as used herein refers to a straight- or branched-chain alkyl moiety and also encompasses unsaturated moieties such as alkenyl and alkynyl groups. The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halogen atoms. The term “halogen” as used herein refers to any of fluorine, chlorine, bromine, or iodine.

[0029] The term "alkoxide" as used herein refers to a -O-alkyl group, i.e. an oxygen atom bonded to an alkyl group, where the oxygen atom is the point of attachment. The term “aminoalkyl” as used herein refers to -NH-alkyl group or a -N(alkyl)2 group, i.e. a nitrogen atom bonded to an alkyl group and a hydrogen, or to two alkyl groups, where the nitrogen atom is the point of attachment. Preferably, the “aminoalkyl” group is a -N(alkyl)2 group.

[0030] The term "aryl" or “arene” as used herein refers to an aromatic carbocyclic ring system. An example of an aryl group includes a group that is a monocyclic aromatic ring system or a polycyclic ring system containing two or more rings, at least one of which is aromatic. Examples of aryl groups include aryl groups that comprise from 1 to 6 exocyclic carbon atoms in addition to ring carbon atoms. Examples of aryl groups include aryl groups that are monovalent or polyvalent as appropriate. Examples of monovalent aryl groups include phenyl, benzyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like. A heteroarene refers to an arene comprising a heterocyclic aromatic ring, for example containing at least one heteroatom selected from oxygen, nitrogen, and sulphur. A “fluoroarene” as referred to herein will accordingly be understood as a species F-Ar, where Ar is an aryl group as described herein.

[0031] The term “cycloalkyl” as used herein refers to a saturated aliphatic hydrocarbyl moiety containing at least one ring, wherein said ring has at least 3 ring carbon atoms. The cycloalkyl groups mentioned herein may optionally have alkyl groups attached thereto. Examples of cycloalkyl groups include groups that are monocyclic, polycyclic (e.g., bicyclic) or bridged ring system. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term “heterocycloalkyl” as used herein refers to a cycloalkyl group wherein the ring contains at least one heteroatom selected from oxygen, nitrogen, and sulphur. Examples of heterocycloalkyl groups include morpholine, piperidine, piperazine and the like.

[0032] The term “metal amide” as used herein refers to a compound formed by the reaction of a metal with ammonia or an amine compound, resulting in the formation of a metal-nitrogen bond. In these compounds, the metal cation is coordinated to one or more amide groups, which consist of a nitrogen atom bonded to one or more organic groups.

[0033] It will be appreciated that certain compounds of formulae (1) and (2) may exist in one or more isomeric (e.g., stereoisomeric) forms. The present disclosure includes all possible stereoisomers, enantiomers, diastereomers, etc. of the compounds described hereinbefore and below. The purification and the separation of isomers may be accomplished by methods known in the art. The present disclosure includes all possible stereoisomers of the compounds described herein as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio.

[0034] Isotopically-labelled compounds are also within the scope of the present disclosure. As used herein, an “isotopically-labelled compound” refers to a presently disclosed compound, such as an organofluorine species, base, fluoride donor species, fluoride acceptor species, or fluorinated species in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36CI, respectively. The method of the present invention may also be useful for fluorinating a fluoride acceptor species with an isotope of fluorine, such as18F. This may be achieved by using an organofluorine species, where the fluorine atom depicted in formula (1), vicinal to the hydrogen depicted in formula (1) is the desired isotope. The present inventors have discovered a surprisingly effective process for fluorination of a fluoride acceptor species using an organofluorine species as the source of fluorine. In particular, the organofluorine species comprises an alkyl chain with a hydrogen atom and a fluorine atom at vicinal positions relative to each other. The vicinal hydrogen and fluorine are eliminated using a base, which provides a fluoride donor species, the fluoride donor species may then donate fluoride to a fluoride acceptor species in order to provide a fluorinated species.

[0035] A first aspect provides a process for fluorination of a fluoride acceptor species comprising: providing an organofluorine species having a structure according to formula (1), wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, alkylamino, or aryl: contacting the organofluorine species with a base to provide a fluoride donor species; and contacting the fluoride donor species with the fluoride acceptor species to form a fluorinated species.

[0036] Alternatively, the first aspect provides a process for fluorination of a fluoride acceptor species comprising: providing an organofluorine species having a structure according to formula (1a), wherein R1, R2, and R3are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, alkylamino, or aryl; contacting the organofluorine species with a base to provide a fluoride donor species; and contacting the fluoride donor species with the fluoride acceptor species to form a fluorinated species. Alternatively, the first aspect provides a process for fluorination of a fluoride acceptor species comprising: providing an organofluorine species, wherein the organofluorine species is an optionally substituted fluoroarene; contacting the organofluorine species with a base to provide a fluoride donor species; and contacting the fluoride donor species with the fluoride acceptor species to form a fluorinated species.

[0037] The organofluorine species may have a structure according to formula (1), which comprises a hydrogen and a fluorine at vicinal positions relative to each other. In the compound of formula (1) the carbon atom bearing said hydrogen is substituted by R1and R2, and the carbon atom bearing said fluorine is substituted by R3and R4.

[0038] The organofluorine species may have a structure according to formula (1a), which comprises a fluoroalkene. Preferably, the compound of formula (1a) is a compound of formula (1 ai) or (1 aii):

[0039] (1 ai) (1aii)

[0040] In the compound of formula (1 ai) R2is a hydrogen and R4is a fluorine, the hydrogen and fluorine are present in a (z) or cis position across a carbon carbon double bond. In the compound of formula (1aii) R3and R4are fluorines. Without being bound to a particular theory, it is thought that the base is able to deprotonate the protic hydrogen atom depicted in formula (1) or (1a).

[0041] Where the organofluorine species is a compound of formula (1a), for example (1 aii), or an optionally substituted fluoroarene, the organofluorine species does not necessarily comprise an acidic hydrogen atom that is suitable for deprotonation. In this case, and without being bound to a particular theory, it is thought that the process for fluorination of a fluoride acceptor species comprises nucleophilic attack of the base into the carbon atom bearing the fluorine atom depicted in formula (1 a) or an aromatic carbon atom bearing a fluorine atom in the optionally substituted fluoroarene. Without being bound to a particular theory, it is thought that the base is able to act as a nucleophile in a nucleophilic vinylic substitution reaction (SNV) or nucleophilic aromatic substitution reaction (SNAr). As will be appreciated, in the case of an organofluorine species not containing an acidic hydrogen atom where the “base” is not expected to act by deprotonation of the organofluorine species, the term “base” may be interchanged with the term “nucleophile”, even where the same compounds are used to fulfil this role.

[0042] The nature of R1to R4are not particularly limited. R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, alkylamino, or aryl. For the avoidance of doubt, any of alkyl, alkoxide, alkylamino, or aryl groups may be substituted with one or more substituents. Preferably, R1, R2, R3and R4may be each independently selected from H, F, substituted or unsubstituted alkyl and substituted or unsubstituted aryl, more preferably, R1, R2, R3and R4may be each independently selected from H, F, and substituted or unsubstituted alkyl. It will be appreciated that any of R1, R2, R3or R4may be bonded to another one of R1, R2, R3or R4in order to provide a cyclic organofluorine species of formula (1) or (1a) for example wherein two of R1, R2, R3or R4are joined to together form a cycloalkyl group.

[0043] Preferably, where any of R1, R2, R3or R4are an alkyl group, the alkyl group is a Ci to C20 alkyl group, preferably a Ci to C10 alkyl group. Preferably, where any of R1, R2, R3or R4are an alkoxy group, the alkoxy group is a -OC1 to C20 alkoxy group, preferably a -OC1 to C10 alkoxy group. Preferably, where any of R1, R2, R3or R4are an aminoalkyl group, the aminoalkyl group is a -NHC1 to C20 aminoalkyl group or -N(Ci to 620)2 aminoalkyl group, preferably a -NHC1 to C10 aminoalkyl group or -N(Ci to 610)2 aminoalkyl group. Preferably, where any of R1, R2, R3or R4are an aryl group, the aryl group is a 6e to 612 aryl group, preferably a 6e aryl group.

[0044] The organofluorine species of formula (1) may be a polymeric organofluorine species so long as a hydrogen is vicinal to a fluoride in satisfaction of formula (1). The organofluorine species of formula (1a) may be a polymeric organofluorine species. In such a case one or more, typically two of the R1, R2, R3or R4will be a polymeric group. For example, suitable polymers for use as the organofluorine species may be selected from polyvinyl fluoride, repeating unit is -(CH2-CHF)-; polyvinylidene fluoride, repeating unit is -(CH2-CF2)-; ethylene tetrafluoroethylene, repeating unit is -(CH2-CH2-CF2-CF2)-; and ethylenechlorotrifluoroethylene, repeating unit is -(CH2-CH2-CFCI-CF2)-. The optionally substituted fluoroarene may be substituted with one or more polymeric substituent.

[0045] Substituent(s) present on R1, R2, R3or R4where these groups are alkyl, alkoxide, alkylamino, or aryl, may be any substituent that is compatible with the reaction conditions. For example, substituents present on R1, R2, R3or R4may be independently selected from, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, fluoro, chloro, bromo, iodo, hydroxy, alkoxy, amino, aminoalkyl, cyano, nitro, and a carbonyl containing group, preferably, substituents present on R1, R2, R3or R4may be independently selected from, Ci to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C2 to C12 cycloalkyl, C5 to C12 cycloalkenyl, C5 to C12 heterocycloalkenyl, Ce to C10 aryl, C2 to C10 heteroaryl, fluoro, chloro, bromo, iodo, hydroxy, -OC1 to C10 alkoxy, amino, -NH(Ci to C10) aminoalkyl, -N(Ci to C )2 aminoalkyl, cyano, nitro, and a Ci to C10 carbonyl containing group.

[0046] Preferably, R1, R2, R3or R4may be optionally substituted with one or more groups selected from F, alkyl, alkoxy, or aryl, more preferably F, Ci to C10 alkyl, Ci to C10 alkoxy, or Ce to C aryl.

[0047] Preferably, R1, R2, R3and R4are each independently selected from H, F, and alkyl or aryl groups, preferably H, F, and fluoroalkyl or fluoroaryl groups, more preferably H, F, and Ci to C10 fluoroalkyl or Ce to C10 fluoroaryl groups.

[0048] Preferably, at least one of R1, R2, R3and R4is F, and more preferably R1, R2, R3and R4are each independently selected from H, F or fluoroalkyl and at least one of R1, R2, R3and R4is F.

[0049] Preferably, the organofluorine species is a hydrofluorocarbon or a polyfluoroalkyl species, for example, HFC-134a (CF3-CFH2), HFC-125 (CF3-CF2H), HFC-143a (CF3-CH3), HFC 152a (CHF2-CH3), or a polyfluoroalkyl species comprising a linear, branched or cyclic carbon chain, wherein each carbon atom is substituted by one or more F atoms. HFC- 134a, HFC-125, HFC-143a, and HFC 152a are all examples of HFCs that are well suited to use in the present invention. Table 1 shows a list of common HFCs.

[0050] Table 1. Common HFCs

[0051] For example, the organofluorine species may be a CFC, such as Cl2C=CF2, CIFC=CF2, CHFCICF3, CI2FC-CH3, CIF2C-CH3, CHCIFCBrF2, CF3CHBrCI, or CF3CF2CHCI2. CFsCHBrCI, also known as halothane (2-bromo-2-chloro-1 , 1 ,1 -trifluoroethane), is used as a general anaesthetic but is a polluting greenhouse gas and ozone depleter. The present invention provides for the recycling of waste halothane.

[0052] Sevoflurane (1 ,1 ,1 ,3,3,3-Hexafluoro-2-(fluoromethoxy)propan) is another anaesthetic which may be used as the organofluorine species in the present invention. Sevoflurane has the structure (CF3)2CH-O-CH2CH2F. Sevoflurane is an example of alkoxide substitution in the organofluorine species.

[0053] 2.3.3.3-Tetrafluoropropene is a refrigerant with low global warming potential which may be used as the organofluorine species of formula (1 a) in the present invention. Similarly,

[0054] 1.3.3.3-Tetrafluoropropene is another example of a refrigerant with low global warming potential which may be used as the organofluorine species of formula (1a).

[0055] 1 ,1 ,1 ,2,2,3,3,4,4,5,5,6,6,7,7-pentadecafluoroheptane is a particularly suitable organofluorine species, the structure of which is given below.

[0056] 1 ,1 ,1 ,2,2,3,3,4,4,5,5,6,6,7,7-pentadecafluoroheptane

[0057] 1 , 1 , 1 ,2,2,3,3,4,4,5,5,6,6,7,7-pentadecafluoroheptane may be prepared by decarboxylation of perfluorooctanoic acid, which is a polyfluoroalkyl substance known for its environmental persistence and use in various products like non-stick cookware and stain-resistant coatings. Optionally, the processes, or uses, of the present invention may comprises a preceding step of decarboxylating a fluorocarboxylic acid, preferably a perfluorocarboxylic acid, more preferably perfluorooctanoic acid, to provide the fluorinated species. An exemplary preparation of 1 , 1 ,1 , 2, 2, 3, 3, 4, 4, 5, 5, 6, 6,7,7- pentadecafluoroheptane by decarboxylation of perfluorooctanoic acid is outlined in example 11.

[0058] The organofluorine species that may be an optionally substituted fluoroarene, for example, an optionally substituted fluorobenzene. The nature of the optional substitution is not particularly limited. For example, the fluoroarene, in addition to the fluorine substituent, may comprise 1 to 5 additional substituents selected from -Ci to C20 alkyl, -C2 to C20 alkenyl, -C2 to C20 alkynyl, -C3 to C20 cycloalkyl, -Ce to C10 aryl, -C3 to C10 heteroaryl, -Ci to C20 alkyloxy -Ci to C20 alkyamino, -OH, -NH2, -ON, -NO2, -F, -Cl, -Br, and -I. Preferably, the optionally substituted fluoroarene is unsubstituted except for the fluoride substituent, more preferably the fluoroarene is a fluorobenzene. By way of example, the fluoroarene may comprise C6Fe, C5F5N or CeHsF.

[0059] Various compounds of formula (1), (1a) and optionally substituted fluoroarenes are commercially available and are preparable by methods known to the skilled person. For example, a particularly preferred subclass of compounds of formula (1) are those wherein R3and R4are fluorine, and wherein R1and R2are independently selected from substituted or unsubstituted aryl groups, preferably the same substituted or unsubstituted aryl group. Such a compound may be prepared by reaction of trifluoroacetaldehyde methyl hemiacetal with the desired aryl-H groups in the presence of a triflic acid or boron trifluoride catalysts.

[0060] Any base may be used so long as it is sufficiently basic to deprotonate the hydrogen atom depicted in formula (1) or (1a). As will be appreciated, the basicity required will vary depending on the nature of R1to R4. For example, the base may have conjugate acid having a pKa of 10 or more, preferably 15 or more, more preferably 20 or more, even more preferably 25 or more, even more preferably 30 or more, most preferably 35 or more. It is also preferable that the base is a non-nucleophilic base.

[0061] Various types of base may be used for this purpose, for example, neutral bases or ionic bases having the formula [B“][Cat+], wherein [B“] is a basic anion and [Cat+] is a cation. It will be appreciated that some substances may have some covalent character in the bonding between [B“] and [Cat+], and [B“][Cat+] species that are not entirely ionic in character are also included. Examples of neutral bases suitable for use in the present invention include phosphazenes, guanidine, DABCO (1 ,4-Diazabicyclo[2.2.2]octane), DBU (1 ,8-Diazabicyclo[5.4.0]undec-7-ene), proton sponge (RTM) (1 ,8- Bis(dimethylamino)naphthalene), and 1 ,5-Diazabicyclo(4.3.0)non-5-ene. Suitable phosphazenes include, for example, P2-t-Bu (1 -te / Y-Butyl-2,2,4,4,4- pentakis(dimethylamino)-2A5,4A5-catenadi(phosphazene), P1-t-Bu (tert-Butylimino- tris(dimethylamino)phosphorane, N'-tert-Butyl-N,N,N',N',N",N"-hexamethylphosphorimidic triamide), P2-Et (1 -Ethyl-2, 2,4,4, 4-pentakis(dimethylamino)-2A5,4A5-catenadi-

[0062] (phosphazene), PI-t-Bu-tris(tetramethylene) (tert-Butylimino-tri(pyrrolidino)phosphorane), P4-t-Bu (1-te / Y-Butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)- phosphoranylidenamino]-2A5,4A5-catenadi(phosphazene)), Poly(bis(ethoxy)phosphazene), P1-t-Oct (te / Y-Octylimino-tris(dimethylamino)- phosphorane), or lmino-tris(dimethylamino)phosphorane (N,N,N',N',N",N"-Hexamethyl- phosphorimidic triamide).

[0063] Examples of ionic bases having the formula [B-][Cat+] include metal carbonates, metal hydroxides, metal alkoxides, metal amides, metal hydrides, organometallic bases, and quaternary ammonium hydroxides. Examples of metal carbonates include Na2CO3, I 2CO3, K2CO3, and CS2CO3. Examples of metal hydroxides include LiOH, NaOH, KOH, CsOH, Mg(OH)2, and Ca(OH)2. Examples of metal alkoxides include sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium pentoxide, sodium phenoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium butoxide, potassium pentoxide, potassium phenoxide, rubidium methoxide, rubidium ethoxide, rubidium propoxide, rubidium butoxide, rubidium pentoxide, rubidium phenoxide, caesium methoxide, caesium ethoxide, caesium propoxide, caesium butoxide, caesium pentoxide, and caesium phenoxide. Examples of metal amides include LDA (lithium diisopropyl amide), NaDA (sodium diisopropyl amide), KDA (potassium diisopropyl amide), lithium tetramethylpiperidide, sodium amide (NaNH2), potassium amide (KNH2), lithium amide (LiNH2), LiHMDS (lithium hexamethyldisilazide), NaHMDS (sodium hexamethyldisilazide), KHMDS (potassium hexamethyldisilazide), RbHMDS (rubidium hexamethyldisilazide) and CsHMDS (caesium hexamethyldisilazide). Examples of metal hydrides include LiH, NaH, KH, RbH and CsH. Examples of organometallic bases include Grignard reagents, Reformaskii reagents, butyllithium, phenyllithium, phenylsodium, benzyl potassium (PhCH2K), as well as unsubstituted or substituted sodium cyclopentadiene, potassium cyclopentadiene, rubidium cyclopentadiene and caesium cyclopentadiene. Examples of quaternary amine hydroxides include ammonium hydroxide, tetramethyl ammonium hydroxide, tetraethyl ammonium hydroxide, and tetrabutyl ammonium hydroxide.

[0064] For example [B-] may be selected from hydroxide, hydride, an alkoxide, an azinide (amide ion), and a carbanion. Examples of alkoxide include methoxide, ethoxide, propoxide, butoxide, pentoxide, and phenoxide. Examples of azinides include dialkyl or disilyl amide of formula [NR2-]. Examples of carbanions include carbanions of formula [RsC-] such as [PhCH2~] or cyclopentadienyl. Preferably, [B“] is selected from alkoxides such as tert- butoxide or tert-pentoxide, dialkyl or disilyl amide of formula [NR2~], for example bis(trimethylsilyl)amide, carbanions of formula [RsC-] such as [PhCH2~] or cyclopentadienyl, more preferably [B“] is a bis(trimethylsilyl)amide anion, tert-butoxide, or [PhCH2-].

[0065] For example, [Cat+] may be selected from metal ions or quaternary ammonium salts. Preferably, [Cat+] may be selected from a metal cation, more preferably a metal cation selected from lithium, potassium, sodium, rubidium, caesium, magnesium, calcium or strontium, even more preferably [Cat+] is potassium, sodium, caesium or rubidium, most preferably potassium or caesium, and in particular potassium.

[0066] Preferably, the base is selected from potassium bis(trimethylsilyl)amide, potassium tert- butoxide, or benzyl potassium (PhCF^K), more preferably potassium bis(trimethylsilyl)- amide. Potassium tert-butoxide and potassium bis(trimethylsilyl)amide are particularly preferable, especially in the case that the organofluorine species is a compound of formula (1a) or an optionally substituted fluoroarene which does not comprise an acidic proton suitable for deprotonation by said base. Particularly in examples where the “base” acts as a nucleophile, such as in a SNV or SNAr substitution with fluoroarenes or organofluorines not comprising acid protons, the base / nucleophile may preferably be a metal, preferably potassium, alkoxide (e.g. KOR in which R = alkyl, aryl), amide (e.g. KNR2 in which R = alkyl, aryl, silyl), organophosphide (e.g. KPR2 in which R = aryl, alkyl), hydride (e.g. KH), MCHR2 (e.g. KCHR2 in which R = silyl, aryl), or a cyclic amine.

[0067] Preferably, the fluoride donor species comprises [F“][Cat+],

[0068] For example, the process of contacting the organofluorine species of formula (1) or (1a) with a base to provide a fluoride donor species may form a fluoride donor species and a species of formula (2) or (2a), respectively:

[0069] (2) ■ (2a)

[0070] Wherein R1, R2, R3, and R4are as defined hereinabove in relation to formula (1) or (1 a), or any embodiment described in relation thereto. For the avoidance of doubt, the use of the term ‘respectively’ denotes that contacting the organofluorine species of formula (1) with a base to provide a fluoride donor species may form a fluoride donor species and a species of formula (2); and that contacting the organofluorine species of formula (1a) with a base to provide a fluoride donor species may form a fluoride donor species and a species of formula (2a). Optionally the process may further comprise separating the species of formula (2) or (2a) from the fluorinated species. Alkenes of formula (2) or alkynes of formula (2a) may be commercially valuable compounds and may serve as building blocks in synthesis, for example, in the production of polymers. Separation of species of formula (2) or (2a) from the fluorinated species would be within the capabilities of the skilled person, for example, by traditional methods such as distillation, sublimation or chromatography. Compounds of formula (2) or (2a) may for example be volatile whilst the fluorinated species may be non-volatile, making separation trivial.

[0071] For example, the compound of formula (2) may be a compound of formula (1a) in the case that at least one of R1, R2, R3, or R4is fluorine. For example, the compound of formula (2) may be a compound of formula (1 ai) in the case that at least one of R1, R2, R3, or R4is hydrogen and at least another one of R1, R2, R3, R4in the (Z) or cis position is fluorine. For example, the compound of formula (2) may be a compound of formula (1 aii) in the case that R1and R2and / or R3and R4are fluorine. Optionally, the process for fluorination of a fluoride acceptor species may comprise: providing an organofluorine species having a structure according to formula (1) as defined herein; contacting the organofluorine species with a base to provide a fluoride donor species; and contacting the fluoride donor species with the fluoride acceptor species to form a fluorinated species; wherein the process further comprises forming a species of formula (1a), preferably formula (1 ai) or (1 aii), as defined herein. Preferably the process further comprises a subsequent process for fluorination of a fluoride acceptor species comprising: contacting the organofluorine species of formula (1a), preferably formula (1 ai) or (1 aii), formed in the preceding process with a base to provide a fluoride donor species; and contacting the fluoride donor species with the fluoride acceptor species to form a fluorinated species.

[0072] The fluoride acceptor species may be any electrophilic compound which is capable of accepting a fluoride ion from the fluoride donor. It will be appreciated that the fluoride donor composition may advantageously find use in the fluorination of any suitable acceptor species. Preferably, the fluoride acceptor species is an electrophilic species, and preferably the fluoride acceptor species has the formula [Z]-LG, wherein LG is a leaving group and [Z] is a species covalently bonded to the leaving group, and the fluorination reaction forms the fluorinated species [Z]-F. In some embodiments, the fluoride acceptor is an ionic species and the fluorination reaction displaces the anion of the ionic species to produce a cation-fluoride species (that may be ionic or at least partially covalent). Nonetheless, it will be appreciated that the fluoride acceptor is not H and the fluorination reaction does not include deprotonation by the fluoride to form HF.

[0073] For example, the fluoride acceptor species may be selected from sulfonyl chlorides, bromides or iodides; a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl chlorides, bromides, iodides, or pseudohalides; activated carboxylic acids, such as, carboxylic acid chlorides, bromides or iodides, imidazolyl amides, acid anhydrides, and carboxylic acid azides; other non-carbon tetragen halides, such as silyl halides, germyl halides, or tin halides; phosphorous halides, and phosphorous oxyhalides; hypervalent organoiodine halides.

[0074] For example, sulfonyl chlorides, bromides or iodides, may be selected from tosyl chloride, mesyl chloride, tosyl bromide, mesyl bromide, 5-(dimethylamino)naphthalene-1 -sulfonyl chloride, methyl 4-(chlorosulfonyl)benzoate, pyridine-4-sulfonyl chloride, pyridine-3- sulfonyl chloride, pyridine-2-sulfonyl chloride, and thiophene-2-sulfonyl chloride.

[0075] For example, alkyl chlorides, bromides, iodides, or pseudohalides, may be selected from Ci to C30 alkyl chlorides, bromides, iodides, mesylates or tosylates. For example, alkenyl chlorides, bromides, iodides, or pseudohalides, maybe selected from C2 to C30 alkenyl chlorides, bromides, iodides, mesylates or tosylates. For example, alkynyl chlorides, bromides, iodides, or pseudohalides, maybe selected from C2 to C30 alkynyl chlorides, bromides, iodides, mesylates or tosylates. For example, cycloalkyl chlorides, bromides, iodides, or pseudohalides, may be selected from C3to C30 cycloalkyl chlorides, bromides, iodides, mesylates or tosylates. For example, heterocycloalkyl chlorides, bromides, iodides, or pseudohalides, may be selected from C5 to C30 heterocycloalkyl chlorides, bromides, iodides, mesylates or tosylates. For example, aryl chlorides, bromides, iodides, or pseudohalides, may be selected from Ce to C12 aryl chlorides, bromides, iodides, mesylates or tosylates. For example, heteroaryl chlorides, bromides, iodides, or pseudohalides, may be selected from C2 to C12 heteroaryl chlorides, bromides, iodides, mesylates or tosylates. Any of these groups may be substituted or unsubstituted, for example with any of the substituents described hereinabove. A particularly suitable class of substituted alkyl chlorides, bromides, and iodides are alpha-chloro ketones, alphabromo ketones, or alpha-iodo ketones.

[0076] For example, activated carboxylic acids may be selected from substituted or unsubstituted aryl acid chlorides, bromides, or iodides, such as benzoyl chloride, benzoic acid bromide, benzoic acid iodide, 2,4,6-trimethyl benzoic acid chloride, 2,4,6-trimethyl benzoic acid bromide, 2,4,6-trimethyl benzoic acid iodide, 2,6-difluoro benzoic acid chloride, 2,6-difluoro benzoic acid bromide, 2,6-difluoro benzoic acid iodide, 4-chloro benzoic acid chloride or 4-bromo benzoic acid chloride. For example, activated carboxylic acids may be selected from substituted or unsubstituted alkyl or alkenyl acid chlorides, bromides, or iodides, such as acyl chloride, acyl bromide, acyl iodide, pivalic acid chloride, pivalic acid bromide, pivalic acid iodide, acrylic acid chloride, acrylic acid bromide, and acrylic acid iodide.

[0077] Silyl halides may be selected from compounds having the formula R3SiX, R2SiX2, RSiX3, SiX4, preferably R3SiX or R2SiX2, more preferably R3SiX; wherein X is independently selected from Cl, Br, or I, preferably Cl; and wherein each R is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, preferably alkyl or aryl groups. Specific examples of silyl halides, include MesSiCI, PhMe2SiCI, PhsSiCI, (terf-butyl)2SiCl2, (terf-butyl)Me2SiCI, ( / so-propyl)3SiCI, and MesSiBr. Germyl halides may be selected from compounds having the formula R3GeX, R2GeX2, RGeX3, GeX4, preferably R3GeX or R2GeX2, more preferably R3GeX; wherein X and R as defined above. Specific examples of germyl halides include MesGeCI, PhsGeCI, and Me2GeCl2. Tin halides may be selected from compounds having the formula RsSnX, R2SnX2, RSnXs, SnX4, preferably RsSnX or R2SnX2, more preferably RsSnX; wherein X and R as defined above. Specific examples of tin halides include MesSnCI, PhsSnCI, and Me2SnCl2.

[0078] Phosphorous halides may be selected from compounds having the formula R2PX, RPX2, or PX3, preferably R2PX, RPX2; wherein X and R as defined above. Specific examples of phosphorous halides include Me2PCI, Ph2PCI, (tert-butyl)2PCI, MePCh, PhPCh, PCI3, PBrs, and PI3. Phosphorous oxyhalides may be selected from compounds having the formula R2POX, RPOX2, or POX3, preferably R2POX, RPOX2; wherein X and R as defined above. Specific examples of phosphorous oxyhalides include Ph2POCI, Me2POCI, PhPOCI2, MePOCh, POCI3, POBr3, an POI3.

[0079] Hypervalent organoiodine halides may be selected from compounds having the formula RIX2, R2IX, RX3 and RX5; wherein X and R as defined above. Optionally wherein one or more of the R groups is bonded to the iodine via an oxygen atom, and / or optionally wherein the two R groups are bonded together to form a heterocyclic ring comprising the iodine atom. Specific examples of hypervalent organoiodine halides include PhICh, 1-chloro-3,3- dimethylbenziodoxole, ICI3, IBrs, ICI5, and IBrs.

[0080] Various other metal chlorides, metal bromides, metal iodides, metalloid chlorides, metalloid bromides, and metalloid iodides may serve as fluoride acceptor species, to prepare metal fluorides or metalloid fluorides.

[0081] In the context of the present disclosure, the term “pseudohalide” refers to an R-(SO2)-O- group wherein R is as defined hereinabove. Preferably “pseudohalide” refers to a tosylate (Me-C6C4-(SO2)-O-), mesylate (Me-(SO2)-O-), or triflate (CF3-(SO2)-O-) group.

[0082] For example, [Z]-LG may comprise any of a C-LG bond, a P-LG bond, a S-LG bond, a Si- LG bond, an l-LG bond, a Ge-LG bond, a B-LG bond, an AI-LG bond, a Ga-LG bond, an In-LG bond, a Sn-LG bond, a Se-LG bond, or a Te-LG bond, preferably a C-LG bond, a P- LG bond, a S-LG bond, a Si-LG bond, an l-LG bond, or a Ge-LG, more preferably, a C-LG bond, a P-LG bond, a S-LG bond. For example, [Z]-LG may comprise a leaving group selected from [Z]-CI, [Z]-Br, [Z]-l , [Z]- N2+, carboxylate such as [Z]-(O)2CRS, for example [Z]-acetate, and [Z]-S(O)sRs, where Rsis alkyl or aryl optionally substituted by one or more F groups, such as [Z]-OTs, [Z]-OMs, or [Z]-OTf.

[0083] For example, [Z]-LG may comprise: R5(O)2S-LG, preferably where LG is Cl, Br or I; R5xC(LG)ywhere x = 2 or 3 and y = 1 or 2; R5(O)C-LG; Ar-LG, where Ar is an aryl group; R5xE(LG)ywhere E = Si or Ge, x = 2 or 3 and y = 1 or 2; or R5xEOy(LG)zwhere E = P or I, x = 1 or 2, y = 0 or 1 , and z = 1 or 2; wherein each R5is independently selected from H, substituted or unsubstituted alkyl or aryl, or alkoxy.

[0084] The fluorinated species formed will typically include a fluorine atom in the place of the X group, or of one or more of the X groups, in the case that multiple X groups are present. Thus, the fluorinated species formed may be a compound corresponding to any of the above-discussed fluoride acceptor species with one or more [LG] or X group replaced with fluorine. Many of these fluorinated species find applications as fluorinating agents in chemical synthesis. For example, fluorinating agents such as sulfuryl fluoride, cyanuric fluoride, IF3, nitrosyl fluoride, nitryl fluoride, and sulphur tetrafluoride. Additionally, certain sulfonyl fluoride compounds useful as enzyme inhibitors, such as tosyl fluoride, mesyl fluoride, methyl 4-(fluorosulfonyl)benzoate, 4-(2-aminoethyl)benzenesulfonyl fluoride, 2- nitrobenzenesulfonyl fluoride, and 5-(dimethylamino)naphthalene-1 -sulfonyl fluoride.

[0085] Preferably, the process comprises contacting the organofluorine species with a base to provide a fluoride donor species and subsequently adding the fluoride acceptor species to the mixture comprising the fluoride donor species to form the fluorinated species. This order of addition is advantageous as certain combinations of base and fluoride acceptor species may react to produce unwanted side products. This can be minimised by first reacting the organofluorine species and the base to provide a fluoride donor species prior to the addition of the fluoride acceptor species. However, the reaction may still advantageously take place in one pot.

[0086] The temperature requirement for the first step of contacting the organofluorine species with a base is not particularly limited. This reaction may proceed at low temperature, although increased temperature may also be used to increase the rate of reaction. Preferably, the step of contacting the organofluorine species with a base is carried out from about 0 °C to about 150 °C, for example from about 20 °C to about 60 °C, such as at ambient temperature. As will be appreciated the ideal temperature for this step may vary depending on the nature of the organofluorine species and the base, and the temperature may be increased in order to aid the reaction between the base and the organofluorine species.

[0087] The temperature requirement for the second step of contacting the fluoride donor species with the fluoride acceptor species is also not particularly limited. Preferably, the step of contacting the fluoride donor species with the fluoride acceptor species is carried out at a temperature of from about 10 °C to about 300 °C, for example from about 30 °C to about 250 °C, such as from about 50 °C to about 150 °C. As will be appreciated the ideal temperature for this step may vary depending on the nature of the fluoride donor species and the fluoride acceptor species.

[0088] Typically, the first step of contacting the organofluorine species with a base will include a molar excess of the base as compared to the organofluorine species. Preferably, the base is contacted with the organofluorine species in a base:organofluorine species molar ratio of from 0.8:1 to 3.5:1 , preferably from 1 :1 to 3:1 , more preferably from 1.3:1 to 2.5:1 such as from 1.5:1 to 2:1.

[0089] Typically, the second step of contacting the fluoride donor species with the fluoride acceptor species will include a molar excess of fluoride donor species as compared to the fluoride acceptor species. Typically, this is achieved by using a molar excess of the organofluorine species as compared to the fluoride acceptor species. Preferably, the fluoride donor species is contacted with the fluoride acceptor species in a fluoride donor species:fluoride acceptor species molar ratio of from 0.8:1 to 3.5:1 , preferably from 1 :1 to 3:1 , more preferably from 1.1 :1 to 2.5:1. Preferably, the molar ratio of organofluorine species:fluoride acceptor species is from om 0.8:1 to 3.5:1 , preferably from 1 :1 to 3:1 , more preferably from 1.1 :1 to 2.5:1. Preferably, the molar ratio of base:fluoride acceptor species is from om 0.8:1 to 3.5:1 , preferably from 1 :1 to 3:1 , more preferably from 1.3:1 to 2.5:1.

[0090] As will be appreciated, some organofluorine species may comprise multiple moieties comprising a C-H vicinal to a C-F, such as a polymeric organofluorine species. Similarly, some fluoride acceptor species may be able to accept more than one fluoride ion, e.g. because two or more [LG] or X groups are present. The skilled person would be able to adjust the molar ratio as is necessary in such scenarios.

[0091] The reaction may take place in any suitable solvent or may be performed neat where the reactants are miscible liquids. Typically, the reaction takes place in a solvent. Typically, the solvent is an aprotic solvent. For example, suitable aprotic solvents include tetrahydrofuran (THF), dioxane, benzene, toluene, xylenes, hexane, petroleum ether, pentane, heptane, diethyl ether, ethyl acetate, tert-butyl dimethyl ether, glyme, diglyme, triglyme, tetraglyme, / V, / V-dimethylformamide (DMF), dimethylsulfoxide (DMSO), sulfolane, / V-methyl-2-pyrrolidone (NMP) or combinations thereof. Ethers and arenes, such as THF, triglyme or benzene are particularly suitable solvents. The dilution of the organofluorine species, base, and fluoride acceptor species has been found to impact the yield of the process. Preferably, the total combined concentration of the organofluorine species, base, and fluoride acceptor species is from 0.01 to 10 mmol / mL, more preferably from 0.04 or 0.10 to 10 mmol / mL, preferably from 0.04 to 1 mmol / mL. It will be appreciated that for a sequential reaction, first between the base and organofluorine species, followed by reaction with the fluoride acceptor, a different solvent may be used for each stage. For example, the base and organofluorine species may be reacted in a first solvent, the solvent removed (for example under reduced pressure), and a second solvent added with the fluoride acceptor species.

[0092] Certain additives may also aid the process. The additive may comprise a phase transfer catalyst. In particular, chelating compounds, such as crown ethers, including aza-crown ethers, or cryptands may aid the process. Without being bound to a particular theory it is thought that the chelating compound stabilises the fluoride donor compound and increases the availability of the fluoride ion to react. Preferably, one or more additives are added to enhance the reactivity of the fluoride donor species with the fluoride acceptor species, for example, a cation chelating agent such as a crown ether or a cryptand. Preferably, the additive is added in the first step of contacting the organofluorine species with a base to provide a fluoride donor species and / or the second step of contacting the fluoride donor species with the fluoride acceptor species to form a fluorinated species. Additive added in the first step may remain present in the second step.

[0093] Examples of crown ethers useful in the present process may include 12-crown-4, 15- crown-5, 18-crown-6, benzo-18-crown-6, dibenzo-18-crown-6, and aza-crown ethers, such as 1 ,4,7-Trimethyl-1 ,4,7-triazacyclononane or 1 ,4,8,11-tetraazacyclotetradecane. [2.2.2]cryptand and 18-crown-6 are particularly preferred additives and are well suited to use with bases where the [Cat+] is potassium. Other sizes of crown ether or cryptand are suited to other bases, depending on the nature of [Cat+], Preferably, the additive is coordinated to the fluoride donor species, for example, to form a fluoride donor species of the formula [Cat+]-Additive[F_], preferably [K+]-Additive[F_], more preferably [K+]-18-crown- 6 [F’]. It will be appreciated that the phase transfer catalyst may nonetheless be any suitable phase transfer catalyst and phase transfer catalysts are known to the skilled person. A phase transfer catalyst may for example comprise a quaternary ammonium salt (e.g. a tetraalkylammonium halide of formula [NR4][X]) or an organic phosphonium salt (e.g. a tetraalkylphosphonium halide of formula [PR4][X]), for example a phase transfer catalyst may comprise benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, tetrabutylammonium bromide, methyltrioctylammonium chloride, or hexadecyltributylphosphonium bromide.

[0094] The additive may be used catalytically. Alternatively, the additive may be in a 1 :1 molar ratio with the base or organofluorine species. The additive may also be used in a large molar excess. Preferably, the molar ratio of base:additive is from 1 :0.1 to 1 :20, more preferably 1 :0.1 to 1 :10. Preferably, the molar ratio of organofluorine species:additive is from 1 :0.1 to 1 :20, more preferably 1 :0.1 to 1 :10.

[0095] Each of the steps of contacting the organofluorine species with a base and contacting the fluoride donor species with the fluoride acceptor species may be carried out for any suitable amount of time. It will be appreciated that the reaction time may be varied depending on the precise species being used. Suitably, the step of contacting the organofluorine species with a base may be carried out for at least 5 minutes, at least 10 minutes or at least 20 minutes for example from 5 to 120 minutes, for example from 10 to 90 minutes, such as from 20 to 60 minutes. Suitably, the step of contacting the fluoride donor species with the fluoride acceptor species may be carried out for at least 5 minutes, at least 20 minutes or at least 40 minutes for example from 5 to 180 minutes, for example from 20 to 120 minutes, such as from 40 to 100 minutes, but can if necessary be extended to more than 24 hours.

[0096] A second aspect provides a process for fluorination of a fluoride acceptor species comprising contacting the fluoride acceptor species with a fluoride donor composition formed from a mixture of: an organofluorine species having a structure according to formula (1), wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: and a base.

[0097] Alternatively, the second aspect provides a process for fluorination of a fluoride acceptor species comprising contacting the fluoride acceptor species with a fluoride donor composition formed from a mixture of: an organofluorine species having a structure according to formula (1a), wherein R1, R2, and R3are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: and a base.

[0098] Alternatively, the second aspect provides a process for fluorination of a fluoride acceptor species comprising contacting the fluoride acceptor species with a fluoride donor composition formed from a mixture of: an organofluorine species wherein the organofluonne species is an optionally substituted fluoroarene; and a base.

[0099] The fluoride acceptor species is as described in the first aspect, or optionally in any embodiments described in relation thereto. The organofluorine species is as described in the first aspect, or optionally in any embodiments described in relation thereto.

[0100] The fluoride donor composition is the composition formed from a mixture of an organofluorine species and a base, wherein the organofluorine species and the base are as described in the first aspect, or optionally in any embodiments described in relation thereto.

[0101] Any of the process steps described in relation to the first aspect, for example, the use of additives, the reaction temperature, molar ratios, solvent, or concentration, etc may be used in the process of the second aspect.

[0102] A third aspect provides the use of a fluoride donor composition as a fluorinating agent, wherein the fluoride donor composition comprises: an organofluorine species having a structure according to formula (1), wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: and a base.

[0103] Alternatively, the third aspect provides the use of a fluoride donor composition as a fluorinating agent, wherein the fluoride donor composition comprises: an organofluorine species having a structure according to formula (1a), wherein R1, R2, and R3are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: and a base.

[0104] Alternatively, the third aspect provides the use of a fluoride donor composition as a fluorinating agent, wherein the fluoride donor composition comprises: an organofluorine species wherein the organofluorine species is an optionally substituted fluoroarene; and a base.

[0105] The fluoride donor composition is as described in the second aspect, or optionally in any embodiments described in relation thereto. Such a composition finds use a fluorinating agent, for example, by forming a C-F, P-F, S-F, l-F, Si-F, Ge-F, Sn-F, Se-F, Te-F, B-F, Al- F, Ga-F, In-F, or Ti-F bond. Any of the fluoride-accepting species described in the first embodiment are suitable substrates for fluorination by a fluoride donor composition of the present invention.

[0106] The fluoride acceptor species is as described in the first aspect, or optionally in any embodiments described in relation thereto. The organofluorine species is as described in the first aspect, or optionally in any embodiments described in relation thereto.

[0107] The fluoride donor composition is the composition formed from a mixture of an organofluorine species and a base, wherein the organofluorine species and the base are as described in the first aspect, or optionally in any embodiments described in relation thereto.

[0108] Any of the process steps described in relation to the first aspect, for example, the use of additives, the reaction temperature, molar ratios, solvent, or concentration, etc. may be utilized as part of the use of the third aspect.

[0109] A fourth aspect provides a system comprising a fluoride donor composition and a fluoride acceptor; wherein the fluoride donor composition comprises an organofluorine species having a structure according to formula (1), wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: and a base; wherein the fluoride donor composition and a fluoride acceptor are not mixed, or are premixed.

[0110] Alternatively, the fourth aspect provides a system comprising a fluoride donor composition and a fluoride acceptor; wherein the fluoride donor composition comprises an organofluorine species having a structure according to formula (1a), wherein R1, R2, and R3are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: and a base; wherein the fluoride donor composition and a fluoride acceptor are not mixed, or are premixed.

[0111] Alternatively, the fourth aspect provides a system comprising a fluoride donor composition and a fluoride acceptor; wherein the fluoride donor composition comprises an organofluorine species wherein the organofluorine species is an optionally substituted fluoroarene; and a base; wherein the fluoride donor composition and a fluoride acceptor are not mixed, or are premixed.

[0112] The fluoride acceptor species is as described in the first aspect, or optionally in any embodiments described in relation thereto. The organofluorine species is as described in the first aspect, or optionally in any embodiments described in relation thereto.

[0113] The fluoride donor composition is the composition formed from a mixture of an organofluorine species and a base, wherein the organofluorine species and the base are as described in the first aspect, or optionally in any embodiments described in relation thereto. The donor composition may further comprise an additive as described in the first aspect.

[0114] A fifth aspect provides a fluorinating agent prepared or preparable by contacting an organofluorine species having a structure according to formula (1) wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: with a base.

[0115] Alternatively, fifth aspect provides a fluorinating agent prepared or preparable by contacting an organofluorine species having a structure according to formula (1a) wherein R1, R2, and R3are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl:

[0116] (1a) ; with a base.

[0117] Alternatively, fifth aspect provides a fluorinating agent prepared or preparable by contacting an organofluorine species wherein the organofluorine species is an optionally substituted fluoroarene; with a base.

[0118] The fluorinating agent is prepared or preparable by contacting an organofluorine species and a base, wherein the organofluorine species and the base are as described in the first aspect, or optionally in any embodiments described in relation thereto. The fluorinating agent is useful in a process of fluorinating a fluoride acceptor species as defined herein.

[0119] Without being bound to a particular theory, it is thought that the fluorinating agent comprises microscopic solid fluoride salt, such as KF, and carbon from the degradation of the organofluorine species. This is outlined in more detail in Example 10 and Figure 6. It is thought that the microscopic solid fluoride salt, such as KF, produced in situ in the reaction of the organofluorine species with the base shows excellent reactivity in the fluorination process of the present invention at least due to its high surface area.

[0120] In the fifth aspect, the base is preferably a potassium base, more preferably potassium hexamethyldisilazide. Preferably, the fluorinating agent comprises solid KF particles having a particle size diameter (d50) of 100 pm or less, preferably 50 pm or less, more preferably 25 pm or less, even more preferably 10 pm or less. The particles may for example be measured along their longest dimension and may be evaluated by scanning electron microscopy (SEM).

[0121] In all of the aspects described herein, the organofluorine species may, in some embodiments, comprise any organofluorine species that can produce a fluoride salt, preferably a potassium fluoride or caesium fluoride, by elimination of F’ on reaction with a base or a nucleophile. It will be appreciated that the reactions may suitably be conducted in a solvent in which the fluoride salt is non-soluble, providing an anhydrous fluoride salt as a microscopic solid, which may act as an advantageous fluorinating agent as described herein. For example, in addition to the organofluorine species described elsewhere herein, the organofluorine species may comprise a fluorine-containing alkene or alkyne susceptible to allylic or propargylic substitution, releasing F’, such as CH2=CH-CF3 or similar compounds. The invention will now be described by reference to the following non-limiting Examples and the Figures.

[0122] EXAMPLES

[0123] Yields were determined by19F NMR using ortho 1 ,2-difluorobenzene as an internal standard.

[0124] The terms “tosyl chloride” and “tosyl fluoride” as used herein refer to 4-methylbenzene-1- sulfonyl chloride and 4-methylbenzene-1 -sulfonyl fluoride, respectively.

[0125] The compound (2,4,6-CeH2F3)2CHCF3 is used to refer to 2,2'-(2,2,2-trifluoroethane-1 ,1- diyl)bis(1 ,3,5-trifluorobenzene), which has the following structure:

[0126] Example 1 - NMR Experiments

[0127] A reaction was performed to show that the deprotonation of a compound of formula (1 ) will provide a compound of formula (2).

[0128] (2,4,6-CeH2F3)2CHCF3 (1 eq) and lithium hexamethyldisilazide (1.1 eq) were dissolved in THF and stirred at room temperature for 45 minutes. Figure 1 shows19F NMR spectra taken before (top) and after (bottom) the reaction. The peaks at approximately -106 ppm (integration of 2) and -109 ppm (integration of 4) in both spectra respectively correspond to the 4-fluoro and the 2- / 6-fluoro substituents on the benzene rings. These peaks remain unchanged by the reaction. In the top spectra of (2,4,6-CeH2F3)2CHCF3 prior to the reaction, the peak at approximately -66 ppm (integration of 3) corresponds to the trifluoromethyl group. As can be seen, in the bottom spectra of the products of the reaction, this peak has been replaced by a new peak at approximately -80 ppm (integration of 2) which corresponds to the difluoro alkene group of the compound of formula (2), F2C=C(2,4,6-CeH2F3)2. As can be seen from the NMR spectra, the yield is quantitative.

[0129] A second reaction was performed to show the fluorination of a fluoride acceptor species.

[0130] (2,4,6-CeH2 Fs^CHCFs C eq.), potassium hexamethyldisilazide (1.5 eq.), and catalytic 18- crown-6 were dissolved in THF and stirred at room temperature for 45 minutes. Tosyl chloride (0.5 eq.) was added, and the mixture stirred for 60 minutes at 100 °C. Figure 2 shows a19F NMR spectrum taken after completion of the reaction. A new peak at 65.661 ppm is highlighted in Figure 2. This peak corresponds to the tosyl fluoride formed by this reaction.

[0131] Example 2 - Fluorination of Tosyl Chloride

[0132] The process of the present disclosure was used to fluorinate tosyl chloride to yield tosyl fluoride as the fluorinated species. A variety of different organofluorine species were tested, along with potassium hexamethyldisilazide (KHMDS) as a base.

[0133] The organofluorine species (1 eq.) and KHMDS (1 .5 eq.) were dissolved in THF and stirred for 30 minutes at 20 °C. Tosyl chloride (0.5 eq.) was added, and the reaction heated to 100 °C and stirred for 60 minutes. The organofluorine species used in the reaction and the corresponding yields of tosyl fluoride are shown in Table 1 below.

[0134] Table 1. Varying the Organofluorine Species

[0135]

[0136] KOfBu used as base and donor derived from PFOA via decarboxylation.

[0137] As can be seen, good yields were obtained across a range of organofluorine species including hydrogen, fluorine, substituted and unsubstituted alkyl, and substituted and unsubstituted aryl substituents at the R1to R4positions. It can also be seen that for an organofluorine species substituted with electron-donating groups, (2,4,6- C6H2(OMe)3)2CHCF3, while for 30 minutes at 20 °C the reaction yield was poor, fluorination was possible by simply increasing the temperature of the first step to 100 °C to aid the base:donor reaction.

[0138] Figure 3 shows a19F NMR spectra of the completed reaction mixture of an experiment using HFC-143a as the organofluorine species. HFC-143a is 1 ,1 ,1 -trifluoroethane. Each peak is labelled with the corresponding fluorine compound. The 1 ,2-difluorobenzene internal standard is also shown.

[0139] Figure 4 shows a19F NMR spectra of the completed reaction mixture of an experiment using HFC-134a as the organofluorine species. HFC-134a is 1 ,1 ,1 ,2-tetrafluoroethane. Each peak is labelled with the corresponding fluorine compound. The 1 ,2-difluorobenzene internal standard is also shown.

[0140] Figure 5 shows a19F NMR spectra of the completed reaction mixture of an experiment using HFC-152a as the organofluorine species. HFC-152a is 1 ,1 -difluoroethane. Each peak is labelled with the corresponding fluorine compound, with the complex multiplet peaks zoomed in. The 1 ,2-difluorobenzene internal standard is also shown.

[0141] Example 3 - Formation of C-F Bonds

[0142] The process of the present disclosure was used to fluorinate various fluoride acceptor compounds containing carbon-halide or carbon-pseudohalide bonds. KHMDS was used as the base. The organofluorine species used is listed in Table 2 below.

[0143] The organofluorine species (1.1 eq.) and KHMDS (1.66 eq.) were dissolved in THF and stirred for 60 minutes at 20 °C. The fluoride acceptor compound (1 eq.) was added, and the reaction heated to 100 °C and stirred for 60 minutes. The organofluorine species used, the fluoride acceptor compound used, and the resulting yield of the corresponding fluorinated species end product are shown in Table 2 below.

[0144]

[0145] Reaction time 21.5 hours.

[0146] ** triglyme as solvent, fluorination for 60 min at 222 °C.

[0147] *** THF as solvent for fluoride donor generation, and DMSO as solvent for fluorination at 130-140 °C.

[0148] **** KOfBu used as base

[0149] As can be seen, the process of the present invention is able to form C-F bonds by fluorinating various carbon-based fluoride acceptor species with a halide (other than fluorine) or a pseudohalide as the leaving group. Alkyl halides and aryl halides are readily fluorinated. Carboxylic acid halides and halides alpha to a ketone are readily fluorinated.

[0150] Example 4 - Non-Carbon-Based Fluoride Acceptor Species

[0151] The process of the present disclosure was used to fluorinate various fluoride acceptor compounds to form Si-F, Ge-F, P-F, S-F, and l-F bonds. (2,4,6-CeH2 Fs^CHCFs was used as the organofluorine species and KHMDS as the base.

[0152] The organofluorine species (1.1 eq.) and KHMDS (1.65 eq.) were dissolved in THF orC6D6 and stirred for 60 minutes at 20 °C. The fluoride acceptor compound (1 eq.) was added, and the reaction heated to 100 °C and stirred for 60 minutes. The organofluorine species used, the fluoride acceptor compound used, and the resulting yield of the corresponding fluorinated species end product are shown in Table 3 below.

[0153] Table 3. Non-Carbon Based Fluoride Acceptor Species

[0154] The process of the present disclosure was able to fluorinate various non-carbon atoms in good yields. It is demonstrated that multiple fluorinations can take place on fluoride acceptor species with more than one leaving group to yield multiple fluorine-substituted fluorinated species. Furthermore, the fluorination of non-carbon atoms was highly tolerant to the substitution present on the acceptor.

[0155] Example 5 - Optimisation of the Base

[0156] The process of the present disclosure was used to fluorinate tosyl chloride using (2,4,6- CeH2F3)2CHCF3 as the organofluorine species and a variety of bases to test the impact of the choice of base upon the yield of the fluorinated species (tosyl fluoride).

[0157] (2,4,6-CeH2F3)2OHCF3 (1.1 eq.) and the base (1.65 eq.) were dissolved in THF and stirred for 75 minutes at 20 °C. Tosyl chloride (1 eq.) was added, and the reaction heated to 100 °C and stirred for 60 minutes. The base used and the resulting yield of tosyl fluoride are shown in Table 4 below.

[0158] Table 4. Effect of Base on Yield of Tosyl fluoride

[0159] Potassium and caesium-based bases provided optimised yields. Nevertheless, the desired reaction is possible with other bases and it will be appreciated that the reaction may be driven to a greater yield by increasing temperature and / or by the addition of additives such as chelating agents, for example, crown ethers, or phase transfer catalysts. For example, a reaction was conducted where (2,4,6-CeH2 Fs^CHCFs (1.1 eq.) and the base (1 .65 eq.) were dissolved in THF and stirred for 75 minutes at 20 °C. Tosyl chloride (1 eq.) was added, and the reaction heated to 100 °C and stirred for 60 minutes.

[0160] Example 6 - Optimisation of Reaction Stoichiometry

[0161] The process of the present disclosure was used to fluorinate tosyl chloride using (2,4,6- CeH2F3)2CHCF3 as the organofluorine species and KHMDS as the base. Different molar ratios of organofluorine species:base were tested to determine the optimum stoichiometry.

[0162] (2,4,6-CeH2F3)2OHCF3 and KHMDS were dissolved in THF and stirred for 75 minutes at 20 °C. Tosyl chloride (1 eq.) was added, and the reaction heated to 100 °C and stirred for 60 minutes. The molar ratio of organofluorine species:base species and the resulting yields of tosyl fluoride are shown in Table 5 below.

[0163] Table 5. minutes at 20 °C.

[0164] Excess base relative to the organofluorine species was beneficial, however, it is believed that where the excess is too large this can lead to detrimental reactions between the base and the fluoride acceptor.

[0165] Example 7 - Optimisation of Reaction Concentration

[0166] The process of the present disclosure was used to fluorinate tosyl chloride using (2,4,6- CeH2F3)2CHCF3 as the organofluorine species and KHMDS as the base. Different total concentrations of the organofluorine species, the base, and the fluoride acceptor species were tested. (2,4,6-CeH2F3)2CHCF3 and KHMDS were dissolved in THF and stirred for 60 minutes at 20 °C. Tosyl chloride was added, and the reaction was heated to 100 °C and stirred for 60 minutes. The mmol of each of the organofluorine species ((2,4,6-CeH2F3)2CHCF3), the base (KHMDS), and the fluoride acceptor species (tosyl chloride), as well as the total concentration of all three of these reactants and the resulting yield of tosyl fluoride are shown in Table 6 below.

[0167] Table 6.

[0168] As can be seen, increased concentration appears to have a beneficial effect on yield. This data also shows that a larger excess of organofluorine species is also beneficial to the yield.

[0169] Example 8 - Solvent Optimisation

[0170] The process of the present invention was used to fluorinate tosyl chloride using (2,4,6- CeH2F3)2CHCF3 as the organofluorine species and KHMDS as the base. Various solvents were tested to determine the effect of the solvent on yields.

[0171] (2,4,6-CeH2F3)2OHCF3 (1.1 eq) and KHMDS (1.65 eq) were dissolved in a solvent and stirred for 60 minutes at 20 °C. Tosyl chloride (1 eq) was added, and the reaction heated at 100 °C and stirred for 60 minutes. The solvent used and the resulting yields of tosyl fluoride are shown in Table 7 below. Table 7. Effect of solvent on yield

[0172] * The fluoride acceptor compound (1 eq) was added and the reaction heated to 60 °C in the solvent for 60 minutes.

[0173] ** The fluoride donor activation occurred for 75 minutes.

[0174] The process may be carried out in various solvents. Ideally, ether-based solvents such as THF, or arenes such as benzene may provide optimum yields. It will be appreciated that the solvent may be suitably selected to match the desired reaction temperature.

[0175] Example 9 - Comparative Example Using KF as a Fluoride Donor Species

[0176] Fluorination of tosyl chloride was performed using a direct source of fluoride (potassium fluoride) for comparative purposes.

[0177] Anhydrous KF (2 eq.) and tosyl chloride (1 eq.) were dissolved in THF and stirred at 100 °C for 60 minutes. The resulting yield of tosyl fluoride was 5 %. This compares to 90 % yield when the (2,4,6-CeH2F3)2CHCF3 I KHMDS mixture is used under equivalent conditions as shown in Example 4, for example.

[0178] Thus, the reaction of the present invention not only provides superior yields across a vast range of fluoride acceptor species but recycles waste materials as the source of fluoride, instead of consuming natural resources. Without wishing to be bound by any particular theory, it is believed that the form of the fluoride donor species formed by the combination of a base and organofluorine species in the present process makes it surprisingly effective as a fluoride donor.

[0179] The nature of the fluorinating agent in the reaction was further studied during the reaction of (2,4,6-C6H2F3)2CHCF3 (1 eq) and potassium hexamethyldisilazide (1.1 eq) dissolved in THF and stirred at room temperature for 45 minutes, e.g. according to Example 1.

[0180] During the course of the reaction to form the corresponding compound of formula (2) from the corresponding compound of formula (1) and KHMDS, a fine precipitate assumed to be anhydrous KF was observed. Redissolving this precipitate in D2O gave a diagnostic19F resonance at 5 = -122.17 ppm, consistent with that expected for KF in aqueous solution (commercial KF: -122.04 ppm). Further characterisation was carried out by powder X-ray diffraction and scanning electron microscopy (SEM) and confirmed that the isolated solid contained anhydrous KF with nanoscopic particle size (Figure 6). The SEM image shown in Figure 6 shows an additional amorphous component, likely to be carbon-based, microanalysis of the solid suggests that it is not only KF but also a small quantity of carbon likely from degradation of the hydrofluorocarbon.

[0181] KF produced was measured through the direct reaction of KHMDS with 1 , 2,2,2- tetrafluoroethane, followed by extraction in D2O and quantification against an internal standard. These experiments demonstrated near quantitative formation of KF (93%) using a 1 :2.5 ratio of KHMDS : CH2FCFs. More than one fluorine atom could be removed from the donor, however, as 15 KF formation of 123% was observed using a 2:1 ratio of KHMDS: CH2FCF3. The isolated solid containing nanoscopic KF proved competent for the fluorination of TsCI to form TsF in 75% yield.

[0182] Without being bound to a particular theory, it is thought that this mixture acts as the fluorinating agent. It appears that the specific properties of this mixture make it a vastly superior fluorinating agent as compared to standard commercial anhydrous KF - see comparative Example 9. ic acid

[0183] Perfluoro octanoic acid is one of the most prominent PFAS of environmental concern. As this compound was initially activated through decarboxylation to form 1 H-pefluoroheptane as shown below, which was used as the organofluorine species for fluorination (see Table 1 , Example 2). trigyme:THF 5:4 60 min, 250 °C

[0184] Example 12 - Use of organofluorine species of formula (1a)

[0185] It has been surprisingly found that alkenes of formula (1a) may be used as the organofluorine species. This was initially discovered by analysing the yields of KF produced by certain organofluorine species of formula (1) which comprised multiple fluorine atoms. It was discovered that such organofluorine species could produce yields of KF that were above the theoretical maximum of 100 %. This suggested that the resulting compound of formula (2), which in some cases is a compound of formula (1a), could also act as an organofluorine species in the process of the present invention. Some examples of this are given in Table 8 below.

[0186] A further experiment was performed using 2,2'-(2,2-difluoroethene-1 , 1 -diyl)bis(1 ,3,5- trifluorobenzene) as the organofluorine species. This reaction yielded KF, which demonstrates that defluorination of such a compound does take place. Furthermore, this reaction also yielded over above the theoretical maximum of 100 %, which suggests that further defluorination is taking place. Without being bound to a particular theory, it is thought that the base is able to act as a nucleophile in a nucleophilic aromatic substitution reaction (SNAr) with the fluoroarene groups present in this organofluorine species. The results of this experiment are also shown in Table 8 below.

[0187] For solid or liquid organofluorine species:

[0188] In a dinitrogen containing glovebox, KHMDS (5.8-12.3 mg, 0.029-0.062 mmol) was dissolved in 0.5 ml THF and transferred to a J Young NMR tube. Organofluorine species (0.030 to 0.033 mmol) in 0.2 ml THF was added to the J Young tube. The tube was inverted several times and the reaction mixture allowed to react for 1 hour. The reaction mixture was concentrated in vacuo inside the J Young tube. D2O (1 ml) and sodium triflate (1 M solution in D2O, 9.88 l) was added. For gaseous organofluorine species:

[0189] KHMDS (9.9 to 36.1 mg, 0.050 to 0.181 mmol) was dissolved in 0.5 ml THF. The reaction mixture was degassed via freeze-pump-thaw technique before the organofluorine species (1 .4 bar, 2.3 ml, 0.130 mmol) was added. The reaction mixture was allowed to react for 1 hour. D2O (1 ml) and sodium triflate (1 M solution in D2O, 16.5 pl) was added. The resulting yields of KF (with respect to limiting reagent, see table for details) were obtained using19F

[0190] NMR spectroscopy. The yields are shown in Table 8 below.

[0191] Table 8. KF yields

[0192] 16.88 ll sodium triflate was added.

Claims

CLAIMS:1 . A process for fluorination of a fluoride acceptor species comprising: providing an organofluorine species having a structure according to formula (1) or (1a), wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: or wherein the organofluorine species is an optionally substituted fluoroarene;, ■ contacting the organofluorine species with a base to provide a fluoride donor species; and contacting the fluoride donor species with the fluoride acceptor species to form a fluorinated species.

2. A process according to claim 1 , wherein R1, R2, R3and R4are each independently selected from H, F, and alkyl or aryl optionally substituted with one or more groups selected from F, alkyl, alkoxy or aryl.

3. A process according to claim 2, wherein R1, R2, R3and R4are each independently selected from H, F, and alkyl or aryl groups, preferably fluoroalkyl or fluoroaryl groups.

4. A process according to any one of the preceding claims, wherein at least one of R1, R2, R3and R4is F, preferably wherein R1, R2, R3and R4are each independently selected from H, F or fluoroalkyl and at least one of R1, R2, R3and R4is F.

5. A process according to any one of the preceding claims, wherein the organofluorine species is a hydrofluorocarbon or a polyfluoroalkyl species, for example, HFC-134a (CF3- CFH2), HFC-125 (CF3-CF2H), HFC-143a (CF3-CH3), HFC 152a (CHF2-CH3), or a polyfluoroalkyl species comprising a linear, branched or cyclic carbon chain, wherein each carbon atom is substituted by one or more F atoms.

6. A process according to any one of the preceding claims, wherein the base comprises [B“][Cat+], wherein [B“] is a basic anion and [Cat+] is a cation.

7. A process according to claim 6, wherein [B“] is selected from alkoxide such as tert- butoxide or tert-pentoxide, dialkyl or disilyl amide of formula [NR2~], for example bis(trimethylsilyl)amide, carbanions of formula [RsC-] such as [PhCH2~] or cyclopentadienyl, preferably [B“] is a bis(trimethylsilyl)amide anion, tert-butoxide, or [PhCH2-].

8. A process according to claim 6 or claim 7, wherein [Cat+] is a metal cation, preferably a metal cation selected from lithium, potassium, sodium, rubidium, caesium, magnesium, calcium or strontium, more preferably [Cat+] is potassium, sodium, rubidium or caesium, most preferably potassium.

9. A process according to any one of claims 6 to 8, wherein the base is selected from potassium bis(trimethylsilyl)amide, potassium tert-butoxide, or benzyl potassium (PhCH2K), preferably potassium bis(trimethylsilyl)amide.

10. A process according to any one of claims 6 to 9, wherein the fluoride donor species comprises [F“][Cat+],11. A process according to any one of the preceding claims wherein contacting the organofluorine species of formula (1) or (1 a), with a base to provide a fluoride donor species forms a fluoride donor species and a species of formula (2) or (2a), respectively:R1- C=C - R3(2) . (2a) optionally wherein the process further comprises separating the species of formula (2) or (2a) from the fluorinated species.

12. A process according to any one of the preceding claims, wherein the fluoride acceptor species is an electrophilic species, preferably wherein the fluoride acceptor species has the formula [Z]-LG, wherein LG is a leaving group and [Z] is a species covalently bonded to the leaving group, and the fluorination reaction forms the fluorinated species [Z]-F.

13. A process according to any one of the preceding claims, wherein [Z]-LG comprises any of a C-LG bond, a P-LG bond, a S-LG bond, a Si-LG bond, an l-LG bond, a Ge-LG bond, a B-LG bond, a, AI-LG bond, a Ga- LG bond, an In- LG bond, a Sn-LG bond, an Se- LG bond, or a Te-LG bond, preferably a C-LG bond, a P-LG bond, a S-LG bond, a Si-LG bond, an l-LG bond, or a Ge-LG.

14. A process according to claim 12 or claim 13, wherein [Z]-LG comprises a leaving group selected from [ZJ-CI, [Z]-Br, [Z]-l, [Z]-N2+, [Z]-(O)2CRS, and [Z]-S(O)3Rswhere Rsis alkyl or aryl optionally substituted by one or more F groups, such as [Z]-OTs, [Z]-OMs, or [Z]-OTf.

15. A process according to any one of claims 12 to 14, wherein [Z]-LG comprises:R5(O)2S-LG, preferably where LG is Cl, Br or I; R5xC(LG)ywhere x = 2 or 3 and y = 1 or 2;R5(O)C-LG;Ar-LG, where Ar is an aryl group;R5xE(LG)ywhere E = Si or Ge, x = 2 or 3 and y = 1 or 2; orR5xEOy(LG)zwhere E = P or I, x = 1 or 2, y = 0 or 1 , and z = 1 or 2; wherein each R5is independently selected from H, substituted or unsubstituted alkyl or aryl, or alkoxy.

16. A process according to any one of the preceding claims, wherein the process comprises contacting the organofluorine species with a base to provide a fluoride donor species and subsequently adding the fluoride acceptor species to the mixture comprising the fluoride donor species to form the fluorinated species.

17. A process according to any one of the preceding claims, wherein the step ofcontacting the organofluorine species with a base is carried out from about 0 °C to about 150 °C, for example from about 20 °C to about 60 °C, such as at ambient temperature.

18. A process according to any one of the preceding claims, wherein the step of contacting the fluoride donor species with the fluoride acceptor species is carried out at a temperature of from about 10 °C to about 300 °C, for example from about 30 °C to about 250 °C, such as from about 50 °C to about 150 °C.

19. A process according to any one of the preceding claims, wherein the base is contacted with the organofluorine species in a base:organofluorine molar ratio of from 0.8:1 to 3.5:1 , preferably from 1 :1 to 3:1 , more preferably from 1.3:1 to 2.5:1.

20. A process according to any one of the preceding claims, wherein one or more additives are added to enhance the reactivity of the fluoride donor species with the fluoride acceptor species, for example a cation chelating agent such as a crown ether or a cryptand.21 . A process for fluorination of a fluoride acceptor species comprising contacting the fluoride acceptor species with a fluoride donor composition formed from a mixture of: an organofluorine species having a structure according to formula (1) or (1a), wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: or wherein the organofluorine species is an optionally substituted fluoroarene;, ■ and a base.

22. A process according to claim 21 , wherein the organofluorine species and / or the base are as defined in any one of claims 2 to 10 or 19, and / or wherein the compositioncomprises one or more additives as defined in claim 20.

23. A process according to claim 21 or claim 22, wherein the fluoride acceptor species is as defined in any one of claims 12 to 15 and / or wherein the process is carried out at a temperature as defined in claim 18.

24. Use of a fluoride donor composition as a fluorinating agent, wherein the fluoride donor composition comprises: an organofluorine species having a structure according to formula (1) or (1a), wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: or wherein the organofluorine species is an optionally substituted fluoroarene;and a base.

25. A system comprising a fluoride donor composition and a fluoride acceptor; wherein the fluoride donor composition comprises an organofluorine species having a structure according to formula (1) or (1a), wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: or wherein the organofluorine species is an optionally substituted fluoroarene;(1) (1a)and a base; wherein the fluoride donor composition and a fluoride acceptor are not mixed, or are pre-mixed.

26. A fluorinating agent prepared or preparable by contacting an organofluorine species having a structure according to formula (1) or (1a) wherein R1, R2, R3and R4are each independently selected from H, halogen, and substituted or unsubstituted alkyl, alkoxide, aminoalkyl, or aryl: or wherein the organofluorine species is an optionally substituted fluoroarene;, ; with a base.

27. The fluorinating agent of claim 26, wherein the organofluorine species and / or the base are as defined in any one of claims 2 to 10.

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